Monday, November 29, 2010

Why so much fuss about Anacetrapib?

I'm a bit puzzled by all the excitement about Merck's new drug, Anacetrapib (MK-0859) that's said to lower risk for cardiovascular disease by lowering bad cholesterol. Earlier this week at the annual meeting of the American Heart Association, researchers presented promising findings on the drug, including results from the phase III DEFINE (Determining the Efficacy and Tolerability of CETP Inhibition with Anacetrapib) trial. The list of disclosures for that abstract is long and fairly shocking. On Wednesday, the results were published online in the NEJM.

The new drug interests me, as an oncologist, because it's an enzyme inhibitor – in some ways like many new and in-the-pipeline cancer treatments. Anacetrapib raises high-density lipoprotein (HDL, a.k.a. "good cholesterol") and lowers low-density lipoprotein (LDL, a.k.a. "bad cholesterol") by interfering with a cholesterol enzyme transfer protein (CETP). The experimental medication is a pill that, based on earlier safety studies, is taken at 100 mg by mouth, once daily. So it's convenient enough.

In some respects, the results of this randomized, placebo-controlled large trial are knock-your-socks-off impressive: patients on the drug had, an average, a more-than doubling of their serum HDL levels, from 41 to 101 mg per deciliter (cho­les­terol units: mil­ligrams per deciliter). At the same time, the HDL shift was just 40 to 46 for patients assigned to the placebo (control). Conversely, LDL levels went down dramatically in patients taking Anacetrapib, from 81 to 45 mg per deciliter on average, and the corresponding drop seen among the control patients was only 82 to 77. These numbers are really terrific, and the results highly significant from a statistical perspective. The study lasted for 76 weeks, i.e. well over a year, and the drug was very-well tolerated according to all published reports.

What's wrong here? Well, it's that we don't know for sure how this new drug affects heart disease and other vascular conditions. In this study, the plasma cholesterol levels were monitored as surrogate markers for risk of atherosclerotic events, but these laboratory parameters are not the same thing as direct measures of disease. It is uncertain if this drug has any impact on mortality, or even on heart attacks, strokes or other clinical endpoints.

In my opinion, we need a lot more information about this new drug before we prescribe it to thousands or millions of people who have hyperlipidemia. Fortunately, as pointed out by Dr. Harlan Krumholz, writing for Forbes, Merck is "doing the right thing" by testing the drug in additional studies now, with clinical endpoints in mind. Still, his enthusiasm for what amount to very favorable blood testing seems extreme in light of the previous experience to which he refers with Pfizer's torcetrapib, a drug of the same class that turned out to have significant side effects, and Merck's previous marketing of Zetia.

According to the New York Times, John Boris, an analyst at Citigroup, wrote in a note to investors on Wednesday that the drug could potentially have sales of more than $1 billion a year. Dr. Steven Nissen, a sometimes cautious leader in the field, found the results encouraging, according to widely-cited comments such as those appearing in the Dow Jones Newswires.

In a few years, we'll see what Merck finds out with the ongoing trials, and if the drug really helps reduce heart attacks and deaths in people with hyperlipidemia.

Meanwhile, for those who are skeptical about cholesterol-lowering drugs and their side effects, as I am for people who have only modestly elevated lipid levels, you might consider the old-fashioned approach of dietary modification. The NIH offers tips for therapeutic lifestyle changes that can help reduce hyperlipidemia in many patients.

This post originally appeared at Medical Lessons, written by Elaine Schattner, ACP Member, a nonpracticing hematologist and oncologist who teaches at Weill Cornell Medical College, where she is a Clinical Associate Professor of Medicine. She shares her ideas on education, ethics in medicine, health care news and culture. Her views on medicine are informed by her past experiences in caring for patients, as a researcher in cancer immunology and as a patient who's had breast cancer.

6 Comments:

I am puzzled how you came to the conclusion that Dr. Krumholz had an extreme amount of enthusiasm for anacetrapib. In his blog post on the Forbes website that you reference, he clearly states that showing an effect on laboratory values -- HDL and LDL, in this case -- is not enough. I quote:

"The torcetrapib experience has had a great influence in this class of drugs ... and perhaps is changing the perspective for a range of drugs that are intended to lower risk. Various recent studies have shown that what happens to patients is not always what we expect from changes in risk factors.

Merck is setting a good example by evaluating the drug in steps, carefully assessing its effect on patients, and not proceeding toward approval before testing the effect of the drug on patient outcomes in a large study. The question is not what the drug does to the lab tests -- but what does it do to the risk of patients. The change in the lab test makes us hopeful -- but cannot tell us what will happen to patients."

Nowhere in Dr. Krumholz's post do I see an extreme or inappropriate amount of enthusiasm for anacetrapib. In fact, it appears to me that the two of you are in agreement on the need to have evidence that the drug reduces the risk of cardiovascular endpoints and death before FDA approval.

Hi Marilyn,The tone of the article, as a whole, is notably upbeat from the start:

"It would be great to have a new drug that had a wonderful effect..."

The second paragraph rich with optimistic words: "...At the (AHA) meeting Merck and other investigators are presenting the results of a very promising drug that may reduce heart risk above and beyond what is possible with drugs like Lipitor..." The piece goes on like this, such that any stated caution gets lost in all the positivity.

Even the article's title - that "Merck Does the Right Thing," and which it's possible the author didn't choose, leads the reader to think this is about something good, which it may or may not be.

I do not believe your characterization is a fair reading of Dr. Krumholz's post. I suggest your readers read Dr. Krumholz's post and decide for themselves.

The title refers to the fact that Merck is planning to conduct a large phase III trial with clinical endpoints. Isn't that what you would like them to do? Isn't that in fact the main point of your post?

The positivity was about the promise of the drug, acknowledging its potential - and the applause for Merck was because they are going to pursue a large scale outcomes trial now rather than try to get approval based on the change in the lipid profile. I am an advocate for the need for studies to assess the effect of interventions on outcomes whenever possible. Marilyn has accurately characterized my position.

My positivity was about the promise of the drug. My applause for Merck was for their decision to pursue an adequately-powered outcomes trial before seeking approval. I am a strong advocate for the use of outcomes trials to evaluate the effect of new drugs on patients whenever possible. Improvements in lipid profiles are not a guarantee that patients will benefit. I tried to make that clear in my contribution to Forbes. Ms. Mann does characterize my position in the blog accurately. I encourage anyone who is interested to read the blog. http://blogs.forbes.com/sciencebiz/2010/11/17/merck-does-the-right-thing/

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